WHITEFISH, MT / April 8, 2014 / There has been a disease steadily filling market headlines recently, and no; it’s not cancer. It’s fatty liver disease, particularly Non-alcoholic Fatty Liver Disease, or NAFLD, regarded by many as the most common non-communicable liver disease worldwide. The disease is a silent killer that often goes undetected until late stages, for which there are no FDA-approved treatments. Biotechs focusing on innovative therapies for varying stages of NAFLD are receiving plenty of deserved media coverage. Hepatology leaders in recent headlines include Intercept Pharmaceuticals, (ICPT), Cempra, Inc. (CEMP), MediciNova, Inc. (MNOV), Galectin Therapeutics (GALT) and Lumena Pharmaceuticals, a company preparing to go public.
A Quick Overview
Some fat in the liver is typically not a big deal, but accumulation of fat leads to inflammation, called Non-Alcoholic Steatohepatitis (NASH), which affects between 2 and 5 percent of the U.S. population. NASH subsequently can progress into scarring of the liver, called fibrosis, and then severe scarring, called cirrhosis, and eventually to liver failure and death. There are many points in this progression at which new therapeutics can target treatment of NAFLD. Aside from Galectin, most companies are focused on early stages of the disease. This can present a bit of a problem because there is not a direct correlation in NAFLD and clinical outcomes. Not all NASH patients will progress to develop late and more severe stages of the disease, nor is it possible to discern which patients will progress.
Intercept dominated the news in January with shares ballooning from around $75 to near $500 in two days after reporting positive results from a phase 2 trial of the company's experimental therapy obeticholic acid (OCA) for NASH. MediciNova announced positive pre-clinical test results from a mouse study showing anti-fibrotic properties of MN-001, sending shares initially jumping from about $2.15 to as high as $5.25 before cooling back to starting levels. MediciNova is preparing to initiate a phase 2 trial of MN-001. Also in very early stages, Cempra’s Solithromycin (CEM-101), a drug candidate in two phase 3 clinical trials for community-acquired bacterial pneumonia, popped on the scene this month with a mouse-model discovery that it has potential as a NASH therapy.
Lumena just finished a $45-million raise and is aiming to add $75 million more as it plans a Nasdaq debut under the ticker “LIVR.” The San Diego-based company is looking to stockpile cash to continue advancements of liver disease drugs LUM001 and LUM002. Lumena has licensed LUM002 from Sanofi (SNY) and expects to report results from a phase 1 trial from NASH in the first half of 2014 and initiate a phase 2 trial in the latter part of the year. Investors will likely be looking for a broad move upward in industry players if the results are positive.
Galectin Therapeutics is developing GR-MD-02 for NASH and taking a unique approach compared to competitors by targeting NASH patients with biopsy-proven advanced fibrosis. Pre-clinical research suggested that the drug has the potential to not only stop the progression of NASH, but to actually reverse some of the fibrotic damage. Additionally, Galectin is initially not using the invasive biopsy process as a biomarker. It is using serum biomarkers, which is supportive of the industry as a whole in defining more accurate diagnostics with less invasive technologies to diagnosis disease progression. Last Monday, Galectin released information from the first cohort in a phase 1 clinical trial, presenting a substantial compilation of clinical data that deserves a closer look.
The Key Takeaways of the Data
First and foremost, GR-MD-02 was shown to be safe and well tolerated with no drug-related serious adverse events reported, the primary endpoint of any phase 1 trial. The initial dose for the first cohort was 2 mg/kg (80 mg/m2), which will be doubled in the second cohort. 8 patients (6 in the treatment arm, 2 in placebo arm) were enrolled in the first cohort, seven of which had stage 3 fibrosis and one with stage 4 fibrosis, and all the patients completed the full protocol.
The trial looked at certain hallmarks of any clinical trial, such as safety and pharmacokinetics, as well as dialing-in the effect of GR-MD-02 by examining a broad spectrum of serum biomarkers of NASH, including composite biomarkers of fibrosis, inflammatory cytokines and ALT levels as a proxy of apoptosis. Galectin’s approach covered the gamut of pathological processes of NAFLD by studying biomarkers pertaining specifically to NASH as well as biomarkers specific to fibrosis and cirrhosis. This analysis provides a wider breadth of knowledge about GR-MD-02, as these stages of liver disease don’t always have congruous details. This is an important aspect of the trial, providing wide-ranging data on the effects in the current study and helping to delineate future research.
Results from the FibroTest, an indirect biomarker of fibrosis, showed a significant reduction in scores, which suggests fibrosis regression in patients treated with GR-MD-02. The ELF (Enhanced Liver Fibrosis) test, considered a direct biomarker of fibrosis that has been shown to be predictive of mortality, showed that scores tended to decrease in patients in the treatment arm, but did not produce a “statistically significant” change because of the small sample size of the study. To that point, the researchers will be looking for additional validation of the trend as enrollment grows throughout the trial.
The study also looked at Hyaluronic Acid (HA) levels, which are known to be elevated in liver fibrosis. In 3 of the 6 patients treated with GR-MD-02, HA levels decreased, essentially consistent with pre-clinical data.
Regarding inflammation, levels of key cytokines associated with the advancement of NASH were evaluated. Elevated levels of these cytokines in NAFLD patients are indicative of lipid accumulation and inflammation of the liver. Patients treated with GR-MD-02 showed about a 25% reduction in levels of interleukin-8 from day 1 to day 56. Levels of interleukin-6 and TNF-alpha levels were also significantly reduced in patients treated with Galectin’s drug, as compared to the placebo group.
A measure of cellular injury looked at ALT and AST, two common enzymes released by the liver cells, as part of the safety profile. It is notable that these serum transaminases are relatively poor as a NASH diagnostic because patients with normal levels of ALT and AST can still have NASH. What is interesting in the data, though, is that two of the treated patients with ALT levels above 100 units/liter showed reductions in ALT levels of 39 U/L and 67 U/L, respectively. Data from these patients were looked at more closely in combination with the impact of GR-MD-02 on cell death biomarker cytokeratin 18, a protein that is known to be predictive of NASH severity.
The two patients that demonstrated a sharp drop in ALT levels also showed a marked decrease in CK-18 levels by the end of the treatment period. Taking things a step further, those two patients also showed significant reduction in FibroTest scores and in levels of the protein lumican, a matrix protein in the liver involved with fibrogenesis. By comparison, treated patients with low ALT levels showed improvement in fibrosis biomarkers, but not in CK-18 levels.
So What Does This All Mean?
The data suggests that Galectin was pretty much right on target with the assessment of GR-MD-02 before the clinical trial began. There appears to be data supporting the drug candidate to slow and potentially reverse tissue damage in patients with NASH with advanced fibrosis, but the trials are still very early and with a limited number of patients. In short, efficacy is never a spoken primary goal of early clinical trials, but the data lends additional confidence of a biological effect of GR-MD-02 even at low doses, while holding a strong safety profile. As Dr. Peter Traber, CEO and President of Galactin, said in a conference call discussing the clinical data, the company is pleased to see “consistent changes in fibrosis markers and inflammatory markers after four infusions of [GR-MD-02].” Secondly, by looking at a wide swath of data, Galectin seems to have gleaned some key information that may better delineate future patient populations with high ALT levels with respect to cellular injury.
Eight clinical sites are now active to begin enrollment of eight more patients for the second cohort, to be treated with a substantially higher dose of GR-MD-02 (4 mg/kg). Galectin said it believes the optimal dose equivalency from mouse studies would be approximately 8 mg/kg in humans, so the increased dose in cohort two should deliver valuable info on that matter. Further, FibroScan(TM), an ultrasonic medical device that measures liver tissue elasticity, has been added to the protocol to assess the effect of the drug. The results from this cohort are expected in July or August.
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SOURCE: TDM Financial